Project Summary: Dr. Nicholas Todd is applying for an NIH Mentored Research Scientist Development Award to achieve three interrelated goals: 1) undergo training to gain expertise in two key areas of neuroscience; 2) develop a novel approach to non-invasive neuromodulation based on targeted delivery of neurotransmitter chemicals to the brain; 3) build a strong foundation from which to launch a career as an independent research scientist. The grant proposal has been tailored to achieve these goals by aligning the mentorship expertise, training program, and research aims. Dr. Todd is a magnetic resonance imaging (MRI) physicist by training with particular experience in MR- guided focused ultrasound (FUS) applications and MR neuroimaging. His ambition is to have a long research career as an independent scientist using the tools of FUS and MRI to further our understanding of brain function and advance treatments for neurological diseases. In order to round out his skill set for such a career, he is now seeking training in two key areas of systems level neuroscience, the neurobiology of brain networks and modern computational methods for analyzing neuroimaging data, and also expertise in the specific area of FUS-mediated blood-brain barrier (BBB) opening. Under exceptional mentorship, Dr. Todd will gain a comprehensive understanding of the neurobiology of the pain network (primary mentor, Dr. David Borsook), become proficient in applying Dynamic Causal Modeling for analysis of neuroimaging data (mentor Dr. Lino Becerra and collaborator Dr. Karl Friston), and become an expert in FUS-mediated BBB opening (mentor Dr. Nathan McDannold). The research aims in the proposal build on Dr. Todd?s experience with MR neuroimaging and FUS applications, while providing him with direct experiences in the areas of training. The research work will develop and validate methodology for a novel approach to non-invasive neuromodulation that uses FUS- mediated BBB opening to deliver neurotransmitters to targeted brain regions. The targeted neurotransmitter delivery method will be used to investigate modulation of the rodent pain network. Excitatory (glutamate) and inhibitory (GABA) neurotransmitters will be delivered to nodes of the pain network (thalamus and somatosensory cortex) in healthy and neuropathic pain rats. The effects will be measured throughout the entire pain network using the three complimentary approaches of functional MRI (fMRI), Dynamic Causal Modeling (DCM), and behavioral testing. This work will advance Dr. Todd along his path towards becoming an independent scientist. The training component will provide Dr. Todd with the necessary knowledge of systems level neuroscience to pursue a career using MRI and FUS for brain related research; the research component will develop a new method for non-invasive neuromodulation that will form the basis of future work and grant applications.